Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial

Abstract

Importance: Unresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied.

Objective: To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC.

Design, setting, and participants: The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019.

Interventions: Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months.

Main outcomes and measures: The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis.

Results: The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event.

Conclusions and relevance: In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy.

Trial registration: ClinicalTrials.gov Identifier: NCT02115464.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr Pond reported receiving grants from the Canadian Institute for Health Research during the conduct of the study and personal fees from Takeda IDMC membership, AstraZeneca, Merck, and Profound Medical outside the submitted work; in addition, Dr Pond has a close family member who works for Roche Canada Ltd and owns stock in Hoffman-La Roche Ltd. Dr Ellis reported receiving honoraria for speaking and serving on an advisory board from AstraZeneca, Eli Lilly and Pfizer, and honoraria for serving on an advisory board from Merck, BMS, Takeda, Jazz outside the submitted work. Dr Swaminath reported honoraria for serving on an advisory board from AstraZeneca, honoraria from Bristol Myers Squibb and Eisai Honorarium for serving on advisory boards outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

ECOG indicates Eastern Cooperative Oncology Group. aOther exclusion criteria met included more than 10% weight loss (n = 3), pulmonary function tests (n = 1), complete blood cell count (n = 1), glucose level (n = 2), congestive heart failure (n = 1), liver disease (n = 1), geographic inaccessibility (n = 3), and lack of consent (n = 2). Patients may have met more than 1 exclusion criterion.

Figure 2.. Progression-free and Overall Survival Outcomes

A, Progression-free survival at 1 year was 34.8% (95% CI, 16.6%-53.7%) in the metformin group and 63.0% (95% CI, 42.1%-78.1%) in the control group. B, Overall survival was 47.4% (95% CI, 26.3%-65.9%) in the metformin group and 85.2% (95% CI, 65.2%-94.2%) in the control group. Plots were generated with a time-to-event intention-to-treat analysis. Events were defined from the date of randomization to date of objective local, regional, or distant progression based on clinical examination or computed tomography, magnetic resonance imaging, or nuclear medicine imaging or to date of death.